30 Years: Our Extraordinary Journey 3 Prologue to an Exciting - - PowerPoint PPT Presentation

30 Years:

Our Extraordinary Journey

3

Prologue to an Exciting Future

4

Novel Business Model

Brian Birchler, 1997

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The Antisense Advantage: The Ionis Business Model and Technology Have Resulted in a Proven, Efficient Platform for Creating New Medicines

TRADITIONAL PHARMA 1 medicine / >1,000 employees IONIS 1 medicine / 11 employees

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Image: Charlie Neuman

An Even More Exciting Future

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Our Technology

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Advances in Our Technology Substantially Improve the Utility of Antisense Medicines

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Time

Advances in Antisense Medicinal Chemistry

Gen 2+

ED50 = 150 mg/wk 1 mL

Gen 2.5

ED50 = 15 mg/wk 0.3 mL

Gen 2+ LICA

ED50 = 4.5 mg/wk 0.1 mL

Gen 2.5 LICA

ED50 = 1 mg/wk < 0.05 mL

▪ Increasing dose flexibility ▪ Increasing potency ▪ Increasing safety and tolerability ▪ Decreasing dose volume ▪ Addressing new tissues

ED50’s and dose volumes are representative of liver targets

2018 Biogen Collaboration

An Example of the Significantly Increasing Value of our Technology

2013 Strategic Neurology Collaboration 2018 Strategic Neurology Collaboration Upfront payment $100 Million $1 Billion* Research term 6 years 10 years Option timing Clinical proof-of-concept Completion of IND-enabling studies Additional payments per typical program Up to $220M Up to $270M Royalty rate Low to mid teens Mid teens to twenty

*Includes $625 million for Ionis stock at 25% cash premium

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AKCEA-ANGPTL3-LRx Metabolic disorders

Medium

IONIS-TTR-LRx Transthyretin amyloidosis

Medium

IONIS-TMPRSS6-LRx b-Thalassemia

Medium

IONIS-GHR-LRx Acromegaly

Small (Rare)

IONIS-PKK-LRx Hereditary angioedema

Small (Rare)

Gen 2.5 Liver LICA

An Example of Advances in Technology Enhancing the Value of Our Pipeline

MEDICINE INDICATION MARKET OPPORTUNITY

AKCEA-APO(a)-LRx Cardiovascular disease

Large

AKCEA-APOCIII-LRx Cardiovascular disease

Large

IONIS-HBV-LRx Hepatitis B virus infection

Large

IONIS-FB-LRx Complement-mediated diseases

Large

IONIS-AGT-LRx Treatment-resistant hypertension

Large

IONIS-FXI-LRx Clotting disorders

Large

ION224 Nonalcoholic steatohepatitis

Large

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2 LIVER-TARGETED Gen 2.5 LICA MEDICINES IN PIPELINE

IONIS-AZ4-2.5-LRx Cardiovascular disease

Potential for commercially attractive

• ral delivery

ION839 Nonalcoholic steatohepatitis

A Broad Chemistry Effort RNase H1 selected as key mechanism Antisense Classification First Proven in vivo Antisense Activities ASO Approach Proposed ASO Optimal Length Selected Vitravene Commercial Failure Alicaforsen Failure

Identification

• f RNase H1

Characterization

• f RNase H1

Vitravene Approval 2’ MOE Discovery

SMA Clinical Trials Initiated

Spinraza Approval / Splicing

Tegsedi Approval Kynamro Approval Further Identification of Mechanisms of Cell Uptake and Intracellular Distribution Prix Galien Award for Spinraza Thrombocytopenia Exploration RNase H1 Mechanism Proven

Tissue targeting (LICA)

Waylivra EU Approval Positive P3 Data in Multiple Studies Initiation of Cardiovascular Program Affinitak Failure Initiation of Neurological Disease Program Initiation of Integrated Safety Data Base

Selection of cET Generation 2.5 Chemistry

Technology Timeline

1990 1993 2003 2005 2007 2009 2011 1998 2000 2014 2016 2018 2004 2006 2008 2010 2013 1992 1996 1999 2001 2015 2017 2019 1989 1978

The Beginning The Early Years The Middle Years The Recent Years

61 Ionis Founded

30 years advancing

• ur technology

Ever-better performance Greater commercial

• pportunities

Ionis: The Leader in RNA-Targeted Drug Discovery Technology, Focused on Innovation and Value Creation

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3 commercial medicines 40+ in development 4+ in Phase 3 planned by YE 2019 10+ in Phase 3 potentially by YE 2020 Pioneer of RNA technology Novel business model Culture of YES

Where is Ionis today?

Annette, living with Charcot Marie Tooth disease

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WAYLIVRA*

▪ Approved in the EU ▪ Earned $6M milestone from PTC Therapeutics for EU approval ▪ EU launch preparations are underway, launching in Germany in Q3 2019

TEGSEDI*

▪ Approved in the U.S., EU and Canada in 2018 ▪ Earned revenue of $9M since launch in late 2018 ▪ NICE authorized pricing and reimbursement in England ▪ Filed and granted priority review in Brazil through PTC Therapeutics

SPINRAZA

▪ The global foundation-of-care for the treatment of people of all ages with spinal muscular atrophy (SMA) ▪ More than $3.1 billion in sales since launch1; Q1 2019 sales increased by 42% compared to Q1 2018 ▪ Over 7,500 patients on treatment2 ▪ Over 1,000 adult SMA patients on SPINRAZA in the U.S., accounted for 50% of new U.S. patient starts1 ▪ Approved in >40 countries, including across Asia and Latin America, with reimbursement in >30 countries3

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Key Recent Achievements

2018 and 2019 (1 of 4)

*Commercialized by Akcea

1As of March 31, 2019 2Includes patients in commercial setting, EAP and clinical trials 3As of April 19, 2019

Pipeline

▪ Advanced 2 medicines into Phase 3 studies; plus 2 medicines on track to enter Phase 3 studies this year ▪ Tofersen (IONIS-SOD1Rx) demonstrated trends towards clinical benefit in measures of disease in a Phase 1/2 study in SOD1-ALS patients ▪ IONIS-HTTRx (RG6042) demonstrated sustained mHTT lowering through 9 months of treatment in the OLE ▪ Earned $150 million when Novartis licensed AKCEA-APO(a)-LRx based on positive Phase 2 data; initiation of Phase 3 cardiovascular outcomes study ongoing ▪ IONIS-DGAT2Rx demonstrated substantial liver fat reductions in patients with type 2 diabetes and NAFLD ▪ Danvatirsen in combination with durvalumab demonstrated a response rate approximately double that of durvalumab alone in a Phase 2 study in patients with head and neck cancer ▪ AKCEA-TTR-LRx continued to progress towards pivotal program, which is on track to start in 2H 2019 ▪ Initiated clinical studies with IONIS-GHR-LRx, IONIS-C9Rx, IONIS-FXI-LRx, IONIS-ENAC-2.5Rx and IONIS-AZ4-2.5-LRx

Key Recent Achievements

2018 and 2019 (2 of 4)

10 *Biogen is collaborating with regulators to further define the scope of the clinical data package required to support the registration of tofersen

Technology

▪ Advanced 3 new chemical classes: Generation 2.5, Generation 2+ LICA, and Generation 2.5 LICA ▪ Enabled respiratory delivery ▪ Discovered new ASO mechanisms ▪ Created new LICAs, e.g. pancreas LICA ▪ Created new chemical approaches that increased therapeutic margins and further improved efficiency

• f ASO drug discovery

Key Recent Achievements

2018 and 2019 (3 of 4)

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Key Recent Achievements

2018 and 2019 (4 of 4)

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Financial

▪ Achieved 7th consecutive year of revenue growth in 2018 ▪ Achieved 3rd consecutive year of non-GAAP operating profitability in 2018 ▪ Cash accretive seven of the last eight years ▪ On track to meet or exceed 2019 guidance of >$725M revenue, >$100M operating income* and net income*

*Non-GAAP, which excludes stock-based compensation – please see reconciliation to GAAP in 1Q19 press release

Delivering Value Today and in the Future

Growing Profits While Investing in Value-Focused Innovation

✓ SPINRAZA ✓ TEGSEDI ✓ WAYLIVRA

TODAY 1 - 2 Years 5 Years

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• Additional commercial

medicines

• Advancing technology
• More tissues, routes
• f administration &

mechanisms

• Growing pipeline

POSITIONED FOR SUBSTANTIAL GROWTH DRIVEN BY…

• 4+ medicines

planned to enter Phase 3 studies by YE19

• 10+ medicines

with potential to enter Phase 3 studies by YE20